Anti-C5a binding moieties with high blocking activity
The present invention relates to binding moieties that specifically bind to a conformational epitope of C5a, in particular human C5a. Preferred binding moieties are anti-C5a antibodies that bind to this conformational epitope. The binding moieties described herein are useful as active agents in pharmaceutical compositions for the treatment and prevention of various acute and chronic diseases, in particular acute inflammatory diseases, such as the systemic inflammatory response syndrome (SIRS), and different degrees of sepsis including sepsis, severe sepsis, and septic shock.
1. An antibody or an antigen-binding fragment thereof comprising a VL and a VH domain, wherein the VL domain comprises a light chain CDR3 sequence having SEQ ID NO: 8, two tyrosine residues preceeding SEQ ID NO: 8 and a light chain FR4 comprising the sequence of SEQ ID NO: 58 or conservative amino acid substitution variants of SEQ ID NO: 58,
wherein said antibody or said antigen-binding fragment thereof specifically binds to human C5a; and
wherein said antibody or antigen-binding fragment thereof has a binding constant to human C5a with a K d value of 100 nM or less.
2. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or said antigen-binding fragment thereof exhibits one or more of the following properties:
said antibody or said antigen-binding fragment thereof has a binding constant to C5a with a K d value of 10 nM or less;
said antibody or said antigen-binding fragment thereof exhibits at least 80% blocking activity for biological effects induced by one molecule C5a, wherein said biological effects are mediated by C5a-05aR interaction;
said antibody or said antigen-binding fragment thereof does not inhibit CH50 activity in human plasma; and
said antibody or said antigen-binding fragment thereof is capable of reducing E. coli induced IL-8 production in human whole blood.
3. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or said antigen-binding fragment is an antibody selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and human antibodies.
4. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or said antigen-binding fragment is an antigen-binding fragment of an antibody selected from the group consisting of Fab fragments, Fab′ fragments, F(ab′) 2 fragments, Fv fragments, disulfide-linked Fvs (dsFv), and single chain Fv (scFv) antibodies.
5. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to claim 1 and further comprising one or more pharmaceutically acceptable carriers, diluents, excipients, fillers, binders, lubricants, glidants, disintegrants, adsorbents, and/or preservatives.
6. A method of blocking C5a-induced biological effects in a patient with acute or chronic inflammation, wherein said method comprises administering to a patient in need of such blocking of C5a-induced biological effects, the pharmaceutical composition of claim 5 .
7. A method for the treatment of a disease involving acute or chronic inflammation, wherein said method comprises administering, to a patient in need of such treatment, the pharmaceutical composition of claim 5 .
8. The method of claim 7 , wherein the disease involving acute or chronic inflammation is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injuries, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reactions, renal glomerular diseases, glomerulonephritis, entities of renal failure, rheumatoid arthritis, auto-immune diseases, Bechterew's disease, lupus-type diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer.
9. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein the conservative amino acid substitution variants of SEQ ID NO: 58 are hydrophobic amino acid substitutions.
10. The antibody or the antigen-binding fragment thereof according to claim 9 , wherein at least one hydrophobic amino acid substitution is a leucine to valine substitution.